Anti-BCMA-CAR-IL15 natural killer cells prevent multiple myeloma growth in the bone marrow but allow subsequent emergence of extramedullary disease

Abstract

Multiple myeloma (MM) is an aggressive blood cancer arising from plasma cells. B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (α-BCMA-CAR-T) immunotherapies currently provide life-saving treatment for MM patients. Unfortunately, the high cost and manufacturing complexity of autologous CAR-T therapy remain important limitations. Novel research is underway to use CAR-expressing natural killer (NK) cells as an allogeneic CAR-T alternative, but studies have yet to evaluate long-term CAR-NK efficacy against MM. In this study, NK cells were isolated, expanded via feeder-cell stimulation, and engineered to express α-BCMA-CAR with or without human IL-15 co-expression using lentiviral vectors. In a xenograft model, both α-BCMA-CAR and IL-15 expression were required for persistent restriction of MM growth in the blood and bone marrow. Despite near complete and sustained elimination of MM in the bone marrow, long-term assessment of mice treated with α-BCMA-CAR-IL15 NK cells revealed the emergence of extramedullary disease (EMD) in the form of BCMA-positive MM plasmacytomas. This study showcases α-BCMA-CAR-IL15 NK cell therapy as a potent anti-MM therapeutic, achieving sustained MM elimination from the bone marrow and greatly extending survival. However, α-BCMA-CAR-IL15 NK cells appeared ineffective at eliminating extramedullary disease. By demonstrating the strengths and weaknesses of α-BCMA-CAR-IL15 cells, we hope this study could help direct the use of such therapies in clinical trials and provide a valuable pre-clinical MM model for studying and developing interventions for aggressive MM-EMD.